THE GENERAL DIAGNOSTICS

OF LIVER DISEASE

László Kalabay MD PhD

Liver diseases 1

Inherited hyperbilirubinemia

• Gilbert’s syndrome

• Crigler-Najjar syndrome I, II

• Rotor syndrome

Viral hepatitis

• A, B, C, D, E, other (EBV, CMV),

cryptogenic

Immune and autoimmune liver

diseases

• Primary biliary cirrhosis (PBC)

• Autoimmune hepatitis (CAH)

• Sclerosing cholangitis (PSC)

• Graft-versus-host disease (GVHD)

• Allograft rejection

Source: Harrison's Principles of Internal

Medicine 18th Ed. McGraw-Hill 2012

Liver involvement in systemic diseases

• Sarcoidosis

• Amyloidosis

• Glycogen storage diseases

• Celiac disease

• Tuberculosis

Cholestatic syndromes

• Benign postoperative cholestasis

• Jaundice of sepsis

• Total parenteral nutrition-induced

jaundice

• Cholestasis of pregnancy

• Cholecystitis and cholangitis

• Extrahepatic biliary obstruction (stone,

stricture, cancer)

• Biliary atresia

• Caroli’s disease

• Cryptosporidiosis

Liver diseases 2

Genetic liver diseases

• α1-antitrypsin deficiency

• Hemochromatosis

• Wilson’s disease

• Benign recurrent intrahepatic

cholestasis (BRIC)

• Progressive familial intrahepatic

cholestasis (PFIC) types I-III

• Others (galactosemia tyrosinemia,

cystic fibrosis, Newman-Pick

disease, Gaucher’s disease)

Alcoholic liver diseases

• Acute fatty liver

• Acute alcoholic hepatitis

• Laënnec’s cirrhosis

• Nonalcoholic fatty liver

• Steatosis

• Steatohepatitis (NASH)

Acute fatty liver of pregnancy

Drug-induced liver disease

• Hepatocellular (INH, acetaminophen)

• Cholestatic (methyltestosterone)

• Mixed (sulfonamides, phenytoin)

• Micro- and macrovesicular steatosis

(MTX, fialuridine)

Vascular injury

• Venoocclusive disease

• Budd-Chiary syndrome

• Ischemic hepatitis

• Passive congestion

• Portal vein thrombosis

• Nodular regenerative hyperplasia

Mass lesions

• Hepatocellular carcinoma (HCC),

cholangiocarcinoma, adenoma, focal

nodular hyperplalsia (FNH), metastatic

tumors, abscess, cysts, hemangiomaSource: Harrison's Principles of Internal Medicine 18th

Ed. McGraw-Hill 2012

History and symptoms

Aspecific constitutional

• Fatigue

• Weakness, malaise

• Nausea, less commonly

vomiting (vomitus

matutinus, too)

• Poor appetite

More liver-specific

• Jaundice

• Dark urine, light stools,

Pruritus (in cholestasis)

• Fever

• Diminished libido

• Anorexia, weight loss

• Abdominal pain, bloating, and

discomfort in the RUQ region

Bloating

• Abdominal swelling (ascites)

• Change in sleep pattern and

behavior

Source: Harrison's

Principles of Internal

Medicine 18th Ed.

McGraw-Hill 2012

Major risk factors for liver disease• Details of alcohol use

• Medications (incl. herbal compounds, birth control pills,

OTC medications)

• Personal habits

• Sexual activity

• Travel

• Exposure to jaundiced or other high-risk persons

• IV drug abuse

• Recent surgery

• Remote or recent transfusion with blood or blood products

• Occupation

• Accidental exposure to blood or needlestick

• Familial history of liver disease

Source: Harrison's

Principles of Internal

Medicine 18th Ed.

McGraw-Hill 2012

Physical examination

Inspection: icterus (sclera, skin) spider teleangiectasias,

palmar erythema, excoriations (pruritus!), xanthomas,

xanthelasmas (hypercholesterinemia), changes in hair

pattern (female type in males), gynecomastia, soft, small

testes, prominence of cutaneous veins, haemorrhoid

veins (portosystemic shunts)

Palpation: size-form-consistency: smooth, nodular, hard,

rockhard, firm-sharp edge, rounded edge, irregular edge,

abdominal mass, tenderness ascites (ballottment)

• cholecyst: Courvosier’s sign

• spleen (splenomegaly in portal hypertension)

Percussion: ascites (as dullness), size and shape of the liver

neurologic examination - flapping tremor

Constellation of

symptoms reported

by patients with

acute hepatitis B

virus (HBV)

Source: Images MD

Icterus

Spider nevi

Source: Medical-On-Line AlamySource: slideshare.net

Ascites

Source: murrasaca.comSource: en.wikipedia.org

Severe protein malnutrition in a patient with

end-stage liver disease

Source: Images MD

Large esophageal varices

Source: Images MD

Pruritus and palmar erythema

Source: Medical-On-Line AlamySource: imgarcade.com

Source: empills.com

Metabolism in liver diseases

CARBOHYDRATE METABOLISM:

• maintenance of blood glucose level in fasting state is

impaired (glycogenolysis, gluconeogenesis)

• glucose intolerance (insulin is diverted to peripheral

circulation via portosystemic shunts)

LIPID METABOLISM:

• in cholestasis, se. cholesterin ↑, phospholipids ↑,

xanthomas, xanthelasmas

AMINO ACID AND PROTEIN METABOLISM:

• albumin (hypalbuminaemia, edema, ascites)

• clotting factors (prothrombin!)

• transferrin

• α1-antitrypsin

BIOTRANSFORMATION AND DETOXIFICATION:

• ammonium → urea (Krebs-Henseleit) = hyperammoniemia

Important diagnostic tests in common liver diseases

Disease Test

Hepatitis A Anti-HAV IgM

Hepatitis B

Acute

Chronic

HBsAg and anti-HBc IgM

HBsAg and HBeAg and/or HBV DNA

Hepatitis C Anti-HCV and HCV DNA

Hepatitis D (delta) HBsAg and anti-HDV

Hepatitis E Anti-HEV

Autoimmune hepatitis ANA, SMA, se. IgG↑, compatible histology

Primary biliary cirrhosis AMA, se. IgM↑, compatible histology

Primary sclerosing cholangitis p-ANCA, cholangiography

Drug-induced liver disease History of drug ingestion

Alcoholic liver disease History and compatible histology

Nonalcoholic steatohepatitis USG or CT evidence of fatty liver, compatible histology

α1 Antitrypsin disease α1-AT levels↓, phenotypes PiZZ or PiSZ

Wilson’s disease Se. ceruloplasmin↓, urinary copper↑, hepatic copper level↑

Hemochromatosis Iron saturation↑, se. ferritin↑, testing for HFE gene mutations

Hepatocellular cancer Elevated AFP > 500; USG or CT image of mass

Source:

Harrison's

Principles of

Internal

Medicine

18th Ed.

McGraw-Hill

2012

A simplified diagnostic approach in patients presenting

with acute hepatitis

Serologic tests of patient's serum Diagnostic interpretation

HBsAg IgM

anti-HAV

IgM

anti-HBc

anti-

HCV

+ - + - Acute hepatitis B

+ - - - Chronic hepatitis B

+ + - - Acute hepatitis A superimposed on

chronic hepatitis B

+ + + - Acute hepatitis A and B

- + - - Acute hepatitis A

- + + - Acute hepatitis A and B (HBsAg

below detection threshold)

- - + - Acute hepatitis B (HBsAg below

detection threshold)

- - - + Acute hepatitis C

Markers of inflammation in liver

disease

• SGOT = serum glutaminic acid-oxalacetic acid

transaminase = ASAT = aspartate

aminotransferase. Present in mitochondria and

cytoplasm.

• SGPT = serum glutaminic acid-pyruvic acid

transaminase = ALAT = aspartate

aminotransferase. Present in cytoplasm.

→ hepatocyte damage

• γ-glutamyl transpeptidase (γGT)

Markers of cholestasis

• Alkaline phosphatase (ALP, SAP)

• Leucine aminopeptidase (LAP)

• 5’-nucleotidase

Tests of protein synthetizing

capacity of the liver

SERUM ALBUMIN AND GLOBULIN:

• albumin decreases (so is colloid osmotic

pressure)

• globulins increase, A/G ↓

PROTHROMBIN TIME:

• vitamin K-dependent clotting factor,

produced exclusively by the liver

Zone

electroph

oresis

pattern in

liver

cirrhosis

Other serum markers of liver disease

• Liver-specific glycoproteins: α2-macroglobulin

• Acute phase reactants:

– positive: C-reactive protein, (CRP), α1-acid

glycoprotein (orosomucoid), serum amyloid A

(SAA)

– negative: albumin, transferrin, fetuin-A

• Serum lipids and lipoproteins

• Elements: iron, copper

Evaluation of

abnormal liver

tests

Source: Harrison's

Principles of Internal

Medicine 18th Ed.

McGraw-Hill 2012

Evaluation of

chronically

abnormal

liver tests

W/U: workup

Source: Harrison's

Principles of Internal

Medicine 18th Ed.

McGraw-Hill 2012

Variant syndromes in autoimmune hepatitis

Source: Images MD

Mitochondrial and smooth muscle

antibodies

Imaging techniques in liver disease

• Ultrasonography

• CT

• MRI

• Angiography

• Fibroscan

Liver

abscess on

abdominal

USG

Source: Images MD

Ultrasound and

liver scan:

hepatic angioma

Source: Images MD

Ultrasound: periportal fibrosis

Source: Images MD

CT: small

hepatocellular

adenoma

(upper) and

cyst (lower) in

the liver

Source: Images MD

Multiple liver abscess

Source: Images MD

Abscess on liver 99Tc

scan

Source: Images MD

MRI: Hepatocellular carcinoma

Source: Images MD

MRI for hepatic metastases of colon cancer

Source: Images MD

Hepatic arteriogram in focal nodular

hyperplasia

Source: Images MD

Portal venography

Source: Images MD

Positron emission tomography for hepatic

metastases of colon cancer

Source: Images MD

Fibroscan - alternative to liver biopsy?

Source: samitivehospital.com

Liver biopsy

A, Prominent portal

inflammation and occasional

peripheral piecemeal necrosis.

B, Section displaying one of

many portal-containing

lymphoid aggregates with

germinal center formation.

Portal lymphoid infiltrates with

germinal center formation,

although not pathognomonic,

occur with relatively increased

frequency in chronic hepatitis

C.

Source: Images MD

Fatty liver (left) and cirrhosis (right)

Source: Images MD

Primary biliary cirrhosis

Source: Images MD

Genetic testing

• HCV infection

• Hemochromatosis (HFE)

• Wilson’s disease (ATP7)

Source: Harrisons's Principles of Internal Medicine 18th Ed. McGraw-Hill 2012

PCR

For the determination of viral copy number

(„viral load”) in hepatitis B and hepatitis C